Full length HCV clones have been produced and shown to be infectious upon transfectin directly into chimpanzee livers. Two chimps were inoculated and both developed HCV infections and disease typical of HCV in chimpanzees following IV inoculation of infectious serum. Both these animals have become chronically infected. As both these animals were infected with clonal virus that was of a single uniform sequence, detailed analyses of the evolution of this virus was possible. It has been claimed that mutations in the hypervariable region of E2 result in escape mutants and allow the persistent infection. We have shown that mutations in the so called hypervariable region of the E2 envelope glycoprotein are not responsible for the maintenance of the persistent infections. Both animals deveoped anti HCV antibody including antibody to the two envelope glycoproteins , E1 and E2, and the the HVR at the amino terminus of E2. The virus in both chimpanzees showed some variabllity over a one year period of observation. After over 3 years of observation, the virus in these chimpanzees has continued to evolve at a slow rate. One additonal mutation has occured in the hypervariable regions of the virus in each animal. however, it is believed that these changes are not sufficient to result in immune escape. Micro array analysis of HCV influence on gene regulation in the liver is being pursued in the chimpanzee model. Prospecitvely collected liver biopsies beginning prior to inoculation are being studied by a high density micro array system with colleagues at Stanford University. The kinetics of HCV infection in the chimpanzee is being studied with Avidan Neumann and others. Using real time quantiative RT-PCR (TaqMan) we have quantitated the HCV RNA in serum at weekly from prior to infection through the actute infection to recovery or into the chronic phase. Mathematical modeling is genreating extremely interesting insights into how HCV replicates and is controlled by host factors including the immune response and interferon.